Results of a comprehensive gene expression analysis suggest that intrafollicular and extrafollicular regions of follicular lymphoma (FL) cells interact with surrounding stroma cells, and may play a significant role in the pathophysiology of FL, according a recent article published in Hematological Oncology. The analysis of these cellular interactions may help in the identification of future therapeutic targets.

FL cells are known to interact heavily with the tumor microenvironment, having associations both with disease progression and treatment resistance. FL generally has a follicular growth pattern, though malignant cells have also been noted in the extrafollicular regions. Given that these regions differ from the microenvironments in which intrafollicular cells thrive, it is likely that extrafollicular cells rely on a different interaction with their own microenvironment to ensure survival.

To determine the differences in gene expression profiles between extrafollicular and intrafollicular regions of FL cells, which may be linked to differences in their respective microenvironments, researchers collected and analyzed cell samples from patients with FL of varying disease grades.

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Overall, specimens from 6 patients were analyzed. The median patient age was 62 years (range, 49-71), 5 were men, 4 had a histological grade of 1 or 2, 2 had a histological grade of 3a, and all 6 patients showed expression in CD10, BCL2, and BCL6. No one showed evidence of MUM1 expression.

Germinal B cell marker genes and BCL2 showed clear distinction between intrafollicular and extrafollicular regions.

Compared with the extrafollicular region, genes related to cell-cycle proliferation were significantly enriched in intrafollicular regions. Conversely, cytokine-related genes were enriched in extrafollicular regions compared with intrafollicular regions, which the authors wrote, may suggest interaction with stroma cells in the extrafollicular region. It is possible that stroma cells in these regions may initiate migration of FL cells to the extrafollicular region

In addition, expression of IL3RA and CXCL12 was greater in extrafollicular regions compared with intrafollicular regions. The authors also noted that IL3RA may be important in supporting FL survival outside of intrafollicular regions.

IL3RA, also known as CD123, is one of the diagnostic markers for blastic plasmacytoid dendritic cell neoplasm (BPDCN) due to its high expression,” the authors wrote. IL3RA is highly expressed in FL, mainly in extrafollicular regions. The investigators also noted that the U.S. Food and Drug Administration has approved an antibody, SL-401, for the treatment for BPDCN, which also shows potential as a therapeutic option for FL; however function analysis is still required.

“In summary, the crosstalk between FL and the tumor microenvironment will be revealed by several techniques under development,” the authors wrote.

Disclosures: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Yoshida N, Miyoshi H, Arakawa F, et al. Cytokine-related genes play critical roles in extrafollicular growth of follicular lymphoma cells. Hematol Oncol. Published online August 24, 2020. doi:10.1002/hon.2795